Krabbe disease, also called globoid cell leukodystrophy (GCL), is a rare, inherited disorder that affects the central nervous system (CNS) and peripheral nervous system. People with Krabbe disease typically have increased muscle tone that causes muscle spasticity and stiffness, impaired motor control, vision problems, seizures, and hearing loss. In many cases, Krabbe disease leads to early death.

Krabbe disease is one of several disorders called leukodystrophies. Leukodystrophies are disorders that affect the growth of development of the myelin sheath, the fatty substance that insulates and protects the nerves in the brain and spinal cord. The myelin sheath continues to develop after birth, with the growth rate peaking before 18 months of age. The myelin sheath is completely developed when a person is about 20 years old. When the myelin sheath does not grow or function properly, it leads to nervous system damage.

People with Krabbe disease have deficient levels of the enzyme galactosylceramidase and as a result, galactolipids build up to toxic levels in the myelin. This causes oligodendrocytes, the cells that produce myelin, to die. Because the myelin is unable to function properly, the nerve cells in the brain and other parts of the body become damaged and destroyed and symptoms of Krabbe disease develop.

Although most people with Krabbe disease develop symptoms before the age of six months, some people may not have noticeable signs of the disease until childhood or adulthood. Based on when symptoms develop, the disease is divided into four major types. Type 1, or infantile Krabbe disease, begins when the infant is three to six months of age. An estimated 85-90% of Krabbe disease cases are classified as type 1. Type 2, or late infantile, typically begins when the baby is six months to three years of age. Type 3, or juvenile Krabbe disease, begins when the child is three to eight years of age. Type 4, or adult-onset Krabbe disease, develops anytime after the age of eight.

It is estimated that one out of 100,000 people worldwide have Krabbe disease. More reports have been documented in a few isolated communities in Israel, where the disease affects about six out of 1,000 people. This is because the disease is hereditary.

There is currently no cure for Krabbe disease. However, if a person undergoes genetic testing and is diagnosed with Krabbe disease before symptoms begin or if symptoms develop later in life, a bone marrow transplant or stem cell transplant may be an effective treatment. In most cases, treatment focuses on reducing symptoms of the disease. Type 1 generally leads to death before age two. Type 2 generally leads to death two years after symptoms develop. Infants who receive umbilical cord stem cells or bone marrow transplants in the early stages of the disease may have a better prognosis. People with types 3 and 4 typically experience milder symptoms and live much longer than infants with type 1 or 2.

General: Most patients with Krabbe disease develop symptoms before the age of six months. However, some people with Krabbe disease may not develop symptoms until childhood or adulthood.

Type 1 (infantile): The infantile form of Krabbe disease generally progresses through three stages.

Stage one typically occurs when the infant is about three to six months of age. The infant's mental and motor development stops and he/she may become irritable and have increased muscle tone that leads to muscle stiffness or tenseness (spasticity). The infant may experience unexplained fevers and have trouble feeding, which may lead to vomiting.

During stage two, which occurs a few months later, nerve cells are rapidly destroyed. This leads to a decrease in muscle control, increased muscle tone, stiffness, impaired vision, and arching of the back. Seizures may start to develop during this stage.

During the third and final stage of the disease, the infant becomes deaf, blind, and completely unaware of his/her surroundings. The baby's rapid mental deterioration eventually leads to death by age two. On average, most babies with type 1 Krabbe disease die by the time they reach 13 months.

Type 2 (late infantile): Type 2 Krabbe disease generally causes the same symptoms as type 1. However, symptoms do not begin to develop until the baby is six months to three years of age. Most children die two years after the initial symptoms develop.

Type 3 (juvenile) and Type 4 (adult-onset): Types 3 and 4 do not cause symptoms until a person has reached childhood or adulthood. People with types 3 and 4 may experience many of the same symptoms as people with types 1 and 2, but the symptoms are often less severe. Muscle weakness is often the primary symptom experienced by people with these types of Krabbe disease. Some people may have no impairment of their cognitive abilities. Additional symptoms may include difficulty walking and loss of manual dexterity.

Blood test: If Krabbe disease is suspected, a blood test may be performed to measure a patient's galactosylceramidase. People with Krabbe disease have low levels of this enzyme in their white blood cells.

Spinal tap: A spinal tap, also called a lumbar puncture, may be performed to measure the levels of galactolipids in the cerebrospinal fluid (CSF). People with Krabbe disease have abnormally high levels of galactolipids in their CSF.

Genetic testing: A DNA test may be performed to confirm a diagnosis of Krabbe disease. However, it is not usually needed. A small sample of the patient's white blood cells is analyzed in a laboratory for mutations in the galactosylceramidase (GALC) gene. If mutations associated with Krabbe disease are found, a positive diagnosis is made.

If a person has a family history of Krabbe disease, a genetic test may be performed to determine if he/she carries a copy of the mutated glucocerebroside gene. Although a carrier does not have Krabbe disease, he/she may pass a copy to his/her children.

Prenatal genetic testing: If a parent is a carrier of the mutated glucocerebrosidase gene, prenatal testing may be performed to determine if the fetus has the disorder. However, there are serious risks associated with prenatal tests. Patients should discuss the potential health benefits and risks associated with these procedures before making any medical decisions.

During amniocentesis, a long, thin needle is inserted into the abdominal wall and into the uterus and a small amount of amniotic fluid is removed from the sac surrounding the fetus. The fluid is then analyzed for a mutated gene. This test is performed after 15 weeks of gestation. Some experts estimate that the risk of miscarriage ranges from one out of 200-400 patients; it is highest when the procedure is done early in pregnancy, before the two layers of fetal membranes have sealed. A woman's particular risk depends in large part on the skill and experience of the doctor performing the procedure. Some patients may experience minor complications, such as cramping, leaking fluid, or irritation where the needle was inserted.

During chorionic villus sampling (CVS), a small piece of tissue (chorionic villi) is removed from the placenta during early pregnancy. Depending on where the placenta is located, CVS can be performed through the cervix or through the abdomen. The tissue sample is then analyzed for a mutated gene. This procedure may be performed between the ninth and 14th week of gestation. The risks of infection or fetal damage are slightly higher than the risks of amniocentesis. Miscarriage occurs in about two percent of women who undergo this procedure. There appears to be an even higher risk of miscarriage with the transcervical CVS technique compared to the transabominal technique. Other factors that further increase the risks involved with CVS include having the procedure performed three or more times and having a fetus that is smaller than normal for their age. The physician's skill and experience also play an important role.

General: People with Krabbe disease typically die from respiratory failure or complications of immobility and increased muscle tone.

Infections: People with Krabbe disease have an increased risk of acquiring infections.

Neurological problems: In the advanced stages of Krabbe disease, particularly types 1 and 2, people experience mental and physical deterioration. Many people become confined to their beds and eventually progress to a vegetative mental state.

Respiratory problems: People with Krabbe disease have an increased risk of developing respiratory problems and breathing difficulties.

General: There is currently no cure for Krabbe disease once symptoms have developed. However, if a person is diagnosed with Krabbe disease before symptoms begin or if symptoms develop later in life, a bone marrow transplant or stem cell transplant may be an effective treatment. In most cases, treatment focuses on reducing the symptoms of the disease.

Bone marrow transplant: A bone marrow transplant, also called a hematopoietic stem cell transplant, may be performed if a person is diagnosed with Krabbe disease before symptoms begin or if symptoms develop later in life. A bone marrow transplant does not appear to be effective for infants. The transplant must come from an adult donor whose blood and body tissues are a close biological match to the recipient.

Serious health risks are also associated with the procedure, as with any major surgery. Individuals who have weakened immune systems are at risk of developing graft-versus-host disease (GVHD) after surgery. This condition occurs when the transplanted bone marrow attacks the recipient's weakened immune system. After a bone marrow transplant, patients typically receive the immunosuppressant drug cyclosporine with or without methotrexate or steroids in order to prevent GVHD.

Cord blood transfusion: A transfusion of blood stem cells, taken from donated umbilical cord blood, has been shown to reduce the neurological symptoms in some infants with Krabbe disease.

In some small studies, babies with Krabbe disease who had not yet developed symptoms of the disease received healthy donor cells that contained normal levels of the galactosylceramidase enzyme. The babies who received treatment were able to develop normal myelin. Infants who received treatment within the first two months of life (before symptoms developed) were able to maintain their hearing and vision. However, they did experience a decline in motor skills.

Early evidence suggests that umbilical cord cells may help treat fetuses who are diagnosed before birth. However, additional research is needed in this area to determine if this is a safe and effective treatment.

Physical therapy: People with juvenile or adult-onset Krabbe disease may benefit from physical therapy. This type of therapy may help improve muscle weakness and help prevent muscle deterioration. A variety of techniques, including exercises, stretches, traction, electrical stimulation, and massage, are used during physical therapy sessions.

Occupational therapy: People with juvenile or adult-onset Krabbe disease who experience mental or physical disabilities may benefit from occupational therapy. The goal of this type of therapy is to provide people with the necessary skills to achieve as much independence as possible. During sessions, a therapist helps the person learn skills to help him/her perform basic daily tasks, such as feeding, dressing, and communicating with others. Some patients work with therapists who specialize in treating disorders and disabilities. Parents and caregivers can ask their children's pediatricians for recommended therapists.

Anticonvulsants: Medications, called anticonvulsants, may be prescribed to treat seizures. These drugs are typically taken once daily to help prevent seizures from occurring. Phenobarbital (Luminal® Sodium) is one of the oldest and safest anticonvulsants for children. Side effects of phenobarbital may include drowsiness, cognitive impairment, and irritability. Valproic acid (Depakene® or Depakote®) has also been shown to be a safe and effective treatment for seizures in children. Side effects of valproic acid may include hepatotoxicity (liver damage), nausea, weight gain, hair loss, and tremors.

There is currently no known method of prevention against Krabbe disease.

If a person has a family history of Krabbe disease, genetic testing may be performed to determine if he/she carries the mutated gene. Although carriers do not have the disease, they can pass a copy of their mutated genes to their children.

Prenatal DNA testing may be performed if there is a family history of Krabbe disease. However, there are health risks associated with prenatal testing, including miscarriage. Therefore, patients should discuss the potential health risks and benefits with their healthcare provider before making any health-related decisions.

Before and after genetic testing, it is recommended that people meet with genetic counselors. These professionals can help patients understand the risks of having a child with Krabbe disease. A genetic counselor can also explain the different types of genetic tests, including their potential risks and benefits. These counselors can help patients understand the results and limitations of these tests.

Individuals with Krabbe disease are born with mutations in the galactosylceramidase (GALC) gene. More than 70 different mutations in this gene have been linked to Krabbe disease. Normally, this gene provides the body with instructions on how to make an enzyme, called galactosylceramidase. This enzyme breaks down certain fats, called galactolipids, which are found in the brain and kidneys. The enzyme is an important component of the myelin sheath, or the fatty substance that protects nerve cells.

Mutations in the GALC gene cause a deficiency of the enzyme galactosylceramidase. This deficiency leads to a progressive loss of myelin, the protective substance that covers nerves. Without myelin, nerves in the brain and other parts of the body do not function normally and symptoms of Krabbe disease develop.

Inheritance: The mutated gene that causes Krabbe disease is passed down from parents to children. Each gene has two variations, called alleles. One allele is inherited from each parent. The mutated gene that causes Krabbe disease is passed down as an autosomal recessive trait. This means that two mutated alleles (one from each parent) of a single gene must be inherited for a person to develop the disease.

Individuals who only have one mutated allele and do not experience symptoms are called carriers. If one parent is a carrier, there is a 50% chance with each birth that a child will also be a carrier and a 0% chance that he/she will inherit the disease. If both parents are carriers, there is a 25% chance with each birth that the child will inherit the disease, and a 50% chance that one of their children will be a carrier.

The information in this monograph is intended for informational purposes only, and is meant to help users better understand health concerns. Information is based on review of scientific research data, historical practice patterns, and clinical experience. This information should not be interpreted as specific medical advice. Users should consult with a qualified healthcare provider for specific questions regarding therapies, diagnosis and/or health conditions, prior to making therapeutic decisions.